Acute hepatitis C virus (HCV) infection results in persistent infection in more than 60% of cases. In contrast, less than 30% of acutely infected patients resolve the infection spontaneously. We have previously shown that the cellular immune response may persist for more than 2 decades in spontaneously recovered patients (Nature Medicine, 6:578, 2000), whereas it is impaired in persistently infected patients. Because these 2 outcomes of infection have also been described in chimpanzees infected with the same doses of clonal HCV, it has been proposed that host rather than viral factors are responsible for the early course of infection. Interestingly, African Americans have been shown to progress to persistent HCV infection more frequently and than Caucasians, but if they do so, develop less severe liver disease. Also, African Americans respond less well to antiviral therapy than Caucasians. This clinical observation would be consistent with a weak cellular immune response of African Americans. To analyze this hypothesis, we are prospectively studying virological markers and HCV-specific immune responses in a cohort of persistently infected African American and Caucasian patients under antiviral therapy. In addition, we are prospectively studying a cohort of health care workers after accidental needlestick exposure to small amounts of HCV. The objective of this study is to analyze the immunological correlates of recovery from hepatitis C prospectively during the early phase of infection. In addition, we have recently described cross-reactivity between HCV and heterologous viruses at the T cell level in infected patients and demonstrated in a transgenic mouse model that HCV NS3-crossreactive T cells can be induced by infection with influenza A virus. Therefore, we are currently analyzing whether the presence of cross-reactive T cells induced by prior exposure to other viruses influences the early HCV-specific immune response. These results may contribute to our understanding of the factors that determine the outcome of HCV infection.